bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020‒10‒11
eleven papers selected by
Joanna Zawacka-Pankau
University of Warsaw


  1. Mol Oncol. 2020 Oct 08.
    Care M, McCuaig J, Clarke B, Grenier S, Kim RH, Rouzbahman M, Stickle N, Bernardini M, Stockley TL.
      The aim of this study was to determine the prevalence of somatic and germline pathogenic variants (PV) in high-grade serous cancer (HGSC) and to demonstrate the technical feasibility and effectiveness of a large-scale, population-based tumor testing program. It involved a retrospective review of genetic test results in 600 consecutive HGSC tumor samples and a subsequent comparison of germline and tumor results in a subset of 200 individuals. Tumor testing was successful in 95% of samples (570/600) with at least one BRCA1/2 PV identified in 16% (93/570) of cases. Among the 200 paired cases, BRCA1/2 PV were detected in 38 tumors (19%); 58% were somatic (22/38) and 42% were germline (16/38). There was 100% concordance between germline and tumor test results. This is the largest series of BRCA1/2 testing in HGSC (tumor-only and paired cohorts), reported to date, and our data shows that an effectively designed and validated population-based tumor testing program can be used to determine both treatment eligibility and hereditary cancer risk.
    Keywords:  BRCA1/BRCA2; germline variant; high-grade serous cancer (HGSC); next-generation sequencing; somatic variant; tumor testing
    DOI:  https://doi.org/10.1002/1878-0261.12817
  2. J Mol Diagn. 2020 Oct 01. pii: S1525-1578(20)30484-0. [Epub ahead of print]
    Rofes P, Menéndez M, González S, Tornero E, Gómez C, Vargas-Parra G, Montes E, Salinas M, Solanes A, Brunet J, Teulé A, Capellá G, Feliubadaló L, Valle JD, Pineda M, Lázaro C.
      RNA analyses are a potent tool to identify spliceogenic effects of DNA variants, although they are time-consuming and cannot always be performed. Here, we present splicing assays of 20 variants representing a variety of mutation types in ten hereditary cancer genes, together with an attempt to incorporate these results into American College of Medical Genetics and Genomics (ACMG) classification guidelines. We selected 16 single-nucleotide variants, 3 exon duplications and one single-exon deletion prioritized by in silico algorithms. RNA was extracted from short-term lymphocyte cultures to perform RT-PCR and Sanger sequencing, and allele-specific expression was assessed whenever possible. We detected aberrant transcripts in 14 variants (70%). We faced the difficulty of variant interpretation comparing old classification standards to generic ACMG guidelines and devised a proposal to weight functional analyses at RNA level. According to ACMG guidelines only 12 were reclassified as pathogenic/likely pathogenic, since the remaining two did not gather enough evidence. Our study highlights the importance of RNA studies to improve variant classification. However, it also evidences the challenge of incorporating these results into generic ACMG guidelines and the need to refine these criteria gene-specifically. Nevertheless, 60% of variants were reclassified, thus improving genetic counseling and surveillance for carriers of these variants.
    DOI:  https://doi.org/10.1016/j.jmoldx.2020.09.007
  3. Clin Cancer Res. 2020 Oct 07. pii: clincanres.1788.2020. [Epub ahead of print]
    Yadav S, Kasi PM, Bamlet WR, Ho TP, Polley EC, Hu C, Hart SN, Rabe KG, Boddicker NJ, Gnanaolivu RD, Lee KY, Lindstrom T, Petersen GM, Couch FJ, McWilliams RR.
      PURPOSE: To compare the clinical characteristics and overall survival (OS) of germline mutation carriers in homologous recombination repair (HRR) genes and non-carriers with pancreatic ductal adenocarcinoma (PDAC).METHODS: Germline DNA from 3,078 patients with PDAC enrolled in a prospective registry at Mayo Clinic between 2000 and 2017 was analyzed for mutations in 37 cancer predisposition genes. Characteristics and OS of patients with mutations in 8 genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, PALB2, RAD51C, and RAD51D) involved in HRR were compared to patients testing negative for mutations in all 37 genes.
    RESULTS: The 175 HRR mutation carriers and 2,730 non-carriers in the study had a median duration of follow-up of 9.9 years. HRR mutation carriers were younger (Median age at diagnosis: 63 vs. 66 years, p<0.001) and more likely to have metastatic disease at diagnosis (46% vs. 36%, p=0.004). In a multivariable model adjusting for sex, age at diagnosis, and tumor staging, patients with germline HRR mutations had a significantly longer OS compared to non-carriers (HR: 0.83, 95% CI: 0.70 to 0.97, p= 0.02). Further gene-level analysis demonstrated that germline ATM mutation carriers had longer OS compared to patients without germline mutations in any of the 37 HRR genes (HR: 0.72, 95% CI: 0.55 - 0.94, p=0.01).
    CONCLUSIONS: This study demonstrates that germline mutation carrier status in PDAC is associated with longer OS compared to non-carriers. Further research into tumor biology and response to platinum-based chemotherapy in germline mutation carriers with PDAC are needed to better understand the association with longer OS.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-1788
  4. Nat Med. 2020 Oct 05.
    Wong M, Mayoh C, Lau LMS, Khuong-Quang DA, Pinese M, Kumar A, Barahona P, Wilkie EE, Sullivan P, Bowen-James R, Syed M, Martincorena I, Abascal F, Sherstyuk A, Bolanos NA, Baber J, Priestley P, Dolman MEM, Fleuren EDG, Gauthier ME, Mould EVA, Gayevskiy V, Gifford AJ, Grebert-Wade D, Strong PA, Manouvrier E, Warby M, Thomas DM, Kirk J, Tucker K, O'Brien T, Alvaro F, McCowage GB, Dalla-Pozza L, Gottardo NG, Tapp H, Wood P, Khaw SL, Hansford JR, Moore AS, Norris MD, Trahair TN, Lock RB, Tyrrell V, Haber M, Marshall GM, Ziegler DS, Ekert PG, Cowley MJ.
      The Zero Childhood Cancer Program is a precision medicine program to benefit children with poor-outcome, rare, relapsed or refractory cancer. Using tumor and germline whole genome sequencing (WGS) and RNA sequencing (RNAseq) across 252 tumors from high-risk pediatric patients with cancer, we identified 968 reportable molecular aberrations (39.9% in WGS and RNAseq, 35.1% in WGS only and 25.0% in RNAseq only). Of these patients, 93.7% had at least one germline or somatic aberration, 71.4% had therapeutic targets and 5.2% had a change in diagnosis. WGS identified pathogenic cancer-predisposing variants in 16.2% of patients. In 76 central nervous system tumors, methylome analysis confirmed diagnosis in 71.1% of patients and contributed to a change of diagnosis in two patients (2.6%). To date, 43 patients have received a recommended therapy, 38 of whom could be evaluated, with 31% showing objective evidence of clinical benefit. Comprehensive molecular profiling resolved the molecular basis of virtually all high-risk cancers, leading to clinical benefit in some patients.
    DOI:  https://doi.org/10.1038/s41591-020-1072-4
  5. Int J Gynecol Pathol. 2020 Oct 05.
    Yoon JY, Apellaniz-Ruiz M, Chong AL, Slim Z, Salfinger SG, Clarke BA, Stewart CJR, Foulkes WD, McCluggage WG.
      Embryonal rhabdomyosarcoma of the uterine cervix is a rare neoplasm which is almost invariably associated with pathogenic somatic or germline DICER1 mutations; patients with germline mutations have DICER1 syndrome. We report 2 subtle cervical embryonal rhabdomyosarcoma, one occurring in a 21-yr-old woman with a known history of DICER1 syndrome and the other in a 19-yr-old woman with no history of DICER1 syndrome or DICER1-associated neoplasms. Both neoplasms focally involved otherwise benign endocervical polyps and were characterized histologically by subtle areas of increased stromal cellularity, nuclear atypia and mitotic activity; there was focal nuclear staining of these areas with the skeletal muscle markers myogenin and myoD1. In both cases, demonstration of a somatic DICER1 RNase IIIb mutation in the tumor was instrumental in establishing the diagnosis. We believe these neoplasms represent the earliest discernible phase of cervical embryonal rhabdomyosarcoma. Pathologists should have a high index of suspicion when atypical stromal elements are present in endocervical polyps and immunohistochemistry together with DICER1 sequencing will assist in diagnosis.
    DOI:  https://doi.org/10.1097/PGP.0000000000000718
  6. Diagnostics (Basel). 2020 Oct 05. pii: E786. [Epub ahead of print]10(10):
    Sobocińska J, Kolenda T, Teresiak A, Badziąg-Leśniak N, Kopczyńska M, Guglas K, Przybyła A, Filas V, Bogajewska-Ryłko E, Lamperska K, Mackiewicz A.
      Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), is a disorder caused by an autosomal dominant heterozygous germline mutation in one of the DNA mismatch repair (MMR) genes. Individuals with LS are at an increased risk of developing colorectal and extracolonic cancers, such as endometrial, small bowel, or ovarian. In this review, the mutations involved with LS and their diagnostic methods are described and compared, as are their current uses in clinical decision making. Nowadays, LS diagnosis is based on a review of family medical history, and when necessary, microsatellite instability (MSI) or/and immunohistochemistry (IHC) analyses should be performed. In the case of a lack of MMR protein expression (dMMR) or MSI-H (MSI-High) detection in tumor tissue, molecular genetic testing can be undertaken. More and more genetic testing for LS is based mainly on next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA), which provide better and quicker information about the molecular profile of patients as well as individuals at risk. Testing based on these two methods should be the standard and commonly used. The identification of individuals with mutations provides opportunities for the detection of cancer at an early stage as well as the introduction of proper, more effective treatment, which will result in increased patient survival and reduced costs of medical care.
    Keywords:  IHC; Lynch syndrome; MLPA; MMR; MSI; NGS; colorectal cancer; diagnostics; hereditary cancer
    DOI:  https://doi.org/10.3390/diagnostics10100786
  7. JAMA Netw Open. 2020 Oct 01. 3(10): e2019452
    Lincoln SE, Nussbaum RL, Kurian AW, Nielsen SM, Das K, Michalski S, Yang S, Ngo N, Blanco A, Esplin ED.
      Importance: Both germline genetic testing and tumor DNA sequencing are increasingly used in cancer care. The indications for testing and utility of these 2 tests differ, and guidelines recommend that germline analysis follow tumor sequencing in certain patients to determine whether particular variants are of somatic or germline origin. Broad clinical experience with such follow-up testing has not yet been thoroughly described.Objective: To examine the yield and utility of germline testing following tumor DNA sequencing in a large, diverse patient population.
    Design, Setting, and Participants: A retrospective cohort study examined germline testing through a laboratory supporting multiple academic and community clinics. Participants included 2023 patients with cancer who received germline testing and previously underwent tumor DNA sequencing. These patients received germline testing between January 5, 2015, and January 31, 2020, although most (81% of patients) received testing between January 2, 2018, and January 31, 2020.
    Main Outcomes and Measures: The prevalence of pathogenic germline variants (PGVs) was calculated by gene, cancer type, and age at diagnosis. Potential actionability of these findings was determined based on current management guidelines, precision therapy labels, and clinical trial eligibility criteria. Patient records were reviewed to determine whether germline follow-up testing would have been recommended by current guidelines.
    Results: Among 2023 eligible patients, 1085 were female (53.6%), and the median age at cancer diagnosis was 56 (range, 0-92) years. Pathogenic germline variants were detected in 617 patients (30.5%; 95% CI, 28.5%-32.6%) and were prevalent across patient ages (1-85 years) and cancer types, including cancers known to be strongly associated with germline variance (eg, breast, colorectal) as well as others (eg, renal, lung, and bladder). Many patients (78%-82%) with PGVs met criteria for germline follow-up testing, and 8.1% of PGVs were missed by tumor sequencing. Among those with germline-positive findings, 69 patients (11.2%) had PGVs identified only after presenting with a second primary cancer that possibly could have been detected earlier or prevented given current gene-specific surveillance and risk-reduction recommendations.
    Conclusions and Relevance: The findings of this study suggest that germline analysis following tumor sequencing often produces findings that may impact patient care by influencing systemic therapy choices, surgical decisions, additional cancer screening, and genetic counseling in families. Current guidelines and tumor testing approaches appear to capture many, but not all, of these germline findings, reinforcing the utility of both expanded germline follow-up testing as well as germline analysis independent of tumor sequencing in appropriate patients.
    DOI:  https://doi.org/10.1001/jamanetworkopen.2020.19452
  8. Horm Mol Biol Clin Investig. 2020 Oct 06. pii: /j/hmbci.ahead-of-print/hmbci-2020-0005/hmbci-2020-0005.xml. [Epub ahead of print]
    Knabben L, Siegenthaler F, Imboden S, Mueller MD.
      Objectives Genetic testing rates for hereditary breast and ovarian cancer (HBOC) have steadily increased during the past decades resulting in a growing population of young and healthy mutation carriers. Available data on fertility issues in BRCA mutation carriers is rising but the results remain to some extent still conflicting. We have performed a systematic literature review in order to get an overview concerning the current evidence on fertility issues in BRCA mutation carriers. Data were analyzed critically with the aim to deliver physicians a solid basis for (onco) fertility counseling in women with BRCA mutations. Content We present the latest data on cancer risks in women with HBOC and analyze the influence of cancer treatment and preventive surgery on the reproductive potential. Epidemiological studies on fertility issues in BRCA mutation carriers showed heterogeneous results. However, several authors showed a decreased ovarian reserve with lower Anti-Müllerien hormone (AMH) levels and poorer response to ovarian stimulation in BRCA positive women. The diagnosis of BRCA mutations influences reproductive decision-making. Additionally, the shortened reproductive window and the need to complete family planning early has a significant psychological impact. Summary and Outlook This article highlights the importance of fertility counseling in BRCA mutation carriers. Individual fertility counseling is mandatory. Fertility preservation strategies should be discussed.
    Keywords:  BRCA mutation carriers; fertility; hereditary breast and ovarian cancer syndrome; premature menopause; reproductive decisions
    DOI:  https://doi.org/10.1515/hmbci-2020-0005
  9. Ann Surg Oncol. 2020 Oct 08.
    Nizic-Kos T, Krajc M, Blatnik A, Stegel V, Skerl P, Novakovic S, Gazic B, Besic N.
      BACKGROUND: Currently, data on pathogenic variants in the CHEK2 gene and their impact on cancer risk are lacking. This study aimed to explore the characteristics of breast cancer (BC) patients from families with CHEK2 pathogenic variants in Slovenia.METHODS: In the years 2014 to 2019, CHEK2 pathogenic variants/likely pathogenic variants (PV/LPVs) were found in probands from 50 different families who underwent genetic counseling and testing using a multigene panel at the authors' institution. Altogether, the study enrolled 75 individuals from 50 CHEK2 families who were carriers of a CHEK2 PV/LPV. The clinical data on 41 BC patients with CHEK2 PV/LPV and other carriers of CHEK2 PV/LPV from Slovenia were collected and analyzed.
    RESULTS: Breast cancer was diagnosed in 41 of 75 CHEK2 PV/LPV carriers (40 females, 1 male). The mean age at BC diagnosis was 42.8 years (range, 21-63 years), and 27 (65.8%) of the 41 of patients with BC had a positive family history for BC. Contralateral BC (CBC) was observed in 8 (19.5%) of the 41 patients (mean age, 55.6 years). Of 12 patients with human epidermal growth factor receptor 2 (HER2)-positive tumor type, a c.444+1G > A PV/LPV was detected in 4 patients, c.349A > G in 3 patients, deletion of exons 9-10 in 3 patients, deletion of exon 8 in 1 patient, and c.1427C > T PV/LPV in 1 patient.
    CONCLUSION: Bilateral BC was diagnosed in as many as 19.5% of the Slovenian BC patients with CHEK2 PV/LPVs. Breast cancer associated with a germline CHEK2 PV/LPV occurs in younger patients compared with sporadic BC.
    DOI:  https://doi.org/10.1245/s10434-020-09178-y
  10. Blood. 2020 Oct 09. pii: blood.2020005756. [Epub ahead of print]
    Duployez N, Jamrog LA, Fregona V, Hamelle C, Fenwarth L, Lejeune S, Helevaut N, Geffroy S, Caillault Venet A, Marceau-Renaut A, Poulain S, Roche-Lestienne C, Largeaud L, Prade N, Dufrechou S, Hébrard S, Berthon C, Nelken B, Fernandes J, Villenet C, Figeac M, Gerby B, Delabesse E, Preudhomme C, Broccardo C.
      In recent years, through whole genome analyses, convincing evidence for the contribution of genetic predisposition to childhood B-cell precursor - acute lymphoblastic leukemia (BCP-ALL) due to altered PAX5 has been provided. A recurrent mutation p.Gly183Ser affecting the octapeptide domain has been described in three unrelated families and a p.Arg38His mutation affecting the DNA-binding paired domain reported in another one. We strengthen here the assumption of the inherited character of familial BCP-ALL by identifying the PAX5 p.Arg38His mutation in a family in which the three children developed BCP-ALL. One relapsed two years after his initial diagnosis and was allografted with his brother's cells before the latter developed BCP-ALL. The patient allografted relapsed later from donor-related cells. By syngeneic transplantations in mice, we showed that p.Arg38His expression does not abrogate the engraftment capacity of transduced Pax5-/- pro-B cells unlike wild type PAX5-rescued Pax5-/- pro-B cells and can predispose to BCP-ALL. Through functional and molecular analyses, we demonstrated that p.Arg38His acts as a hypomorphic variant altering the pattern of expression of PAX5 target genes. Our data highlight the importance of transcriptional deregulation, particularly of genes involved in B cell differentiation in familial BCP-ALL. We demonstrated that inherited genetic basis of susceptibility to BCP-ALL has been underestimated and should be considered before any familial allograft.
    DOI:  https://doi.org/10.1182/blood.2020005756